Yamaguchi Esterification

The Yamaguchi Esterification allows the mild synthesis of highly
functionalized esters. After formation of a mixed anhydride between the
Yamaguchi Reagent (2,4,6-trichlorobenzoyl chloride) and the carboxylic
acid, the volatiles are removed and the reaction of the anhydride with
an alcohol in presence of a stoichiometric amount of DMAP generates the
desired ester.

Mechanism of the Yamaguchi Esterification

Addition of the carboxylate to the carboxylic acid chloride forms the mixed
anhydride:

DMAP is an acyl transfer reagent that reacts regioselectively at the less
hindered carbonyl site:

DMAP is a stronger nucleophile than the alcohol. The newly formed
intermediate is less hindered, the acyl group is still polarized and DMAP is a
good leaving group, all of which enable a fast reaction with the alcohol.

In reactions with aliphatic carboxylic acids, there is no need for a two
step-procedure. It has been shown by SantaLucia, Jr that slight reactivity
differences in this case can even lead to the formation of the symmetric
aliphatic anhydrides, as shown in the following reaction pathway:

I. Dhimitruka, J. SantaLucia, Jr, Org. Lett., 2006, 8, 47-50.

The assumption is that aliphatic carboxylates are better nucleophiles than
either aromatic carboxylates or alcohols. However, the aliphatic anhydride is
also more electrophilic towards DMAP (not shown in the scheme) or the alcohol
than is the aromatic carbonyl of the mixed anhydride produced in situ. A more
detailed description can be found in the work by J. SantaLucia, Jr.